17beta-[n-(aminoalkyl)amino]androstan-3-ols, 5-dehydro derivatives corresponding, and esters thereof



United States Patent 3,084,156 7 B MINOALKYD N J NDR S AN :3.- OLS, S-DEHYDRO DERIYATIVES CORRESPOND- ING, AND ESTERS THEREOF Raymond E. Counsel], Skoliie, and Paul D; Klinistra; Northbro'ok, llL, assignors to G. D. Searle &Co., Chi cago, Ill., a corporation of Delaware No'Drawing. Filed Nov. 30,1961, Ser'. No. 156,136 10 Claims. (Cl.'260-239;5)

The present invention relates to novel 17-substituted aminoalkylamino steroids of the androstane series and, more particularly, to 175-[N-(aminoalkyl')amino]andro'- stan-3'-ols, the corresponding S-d'ehydro derivatives, and esters thereof, which are represented by the structural formula wherein A is hydrogen or a lower alkanoyl radicaL-R is hydrogen or a lower alkyl radical, Alk is a lower alky-lene radical containing more than one carbon atom and separating the -NR and Z functions by at least 2 carbon atoms, the dotted line indicates that the linkage between carbon atoms 5 and 6 can be, alternatively, singly or doubly bonded, the wavy line indicates the alternative or or 5 stereochemical configuration at carbon atom 3,

and Z is a radical selected from the group consisting of RI -N RII and

radicals, wherein R and R can be hydrogen 01- a lower alkyl radical, X is a methylene, epoxy, or (lower alkyl)- irnino radical, and n can be 0 or 1. I

The lower alkyl and lower alkylene radicals encompassed in the structural representation supra are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, ethylene, trimethylene, tetramethylene, pentamethylene, and the branched-chain isomers thereof. Illustrative of the lower alkanoyl group's rep'resehtedby A ar'e'for'myLacetyl, propionyl, buty'ryl, valeryl, oaproyl; afn'd thebriahclied chain groups isomeric therewith;

Suitable starting materials for the manufacture o'fthe compounds of the present invention the 3a and 3B isomers of 3-hydroxyandrost-5-en-17-0116, 3-liydroxy-5aandrostan-l7-on'e, and the lower alka'rioa't'e' e'ste'rs' thereof. Reaction of one of the latter l7-keton'e's with an aminoal-kylamine and formic acid at an elevated temperature ice on, E30

wherein Alk, Z, the dotted line, and the wavy line have the identical meanings recited supra. Reduction of these formamides in a suitablereducing medium such as lithium aluminum hydride afiords tihejinstant compounds wherein R is a methyl radical. On the other hand, hydrolysis of the intermediate renames suitably by heating with a dilute mineral acid such as hydrochloric acid, produces the compounds of this invention wherein R is hydrogen. These two-step processes are specifically illustrated by the reaction of 3fi-hydroxyandrost-5en-l7- one':with '3 dirnethylaminopropylamine and'formic acid at 180 to yield; i'ZB-[N-(Ii-dimethylaminopropyl) forn1 amido]andrOst S-en-B5-01,- which affords 17fl-[N- methyl N (3 dimethylaminopropyl) aminoJandrost-S- en-3p-ol upon reduction with lithium aluminum hydride, and [N-(3-di-methylam inopropyhaniino] androst-S- e'ri-3B-ol upon hydrolysis with hydrochloric acid.

Afi alte'rn'ate' route to the N-alkyl compounds of the present invention involves alkylation of the corresponding compounds possessing a secondaryamino nitrogen at carbon atom 17. For example, 17jB-'[N-( 3-diethylaminopropyl)amino] androst-5-en-3fl-olis allowed to react with formic acid and formaldehyde, resulting in 17,3-[N- methyl N (3'-diethy1aminopropyl)amino]androst-S-en- 33-01.

An alternate process .forthe preparation of the instant compounds wherein R is hydrogen involves condensation of an aforementioned l7-ketone with the appropriate aminoalkyla-mine in'tlie presence ofan acidic catalyst to afford the corresponding imine. Typically, 3,8-acetoxyandrost-5-en-17-one and S-dimethylaniinopropylamine are heated with a catalytic quantityofp tolueiimulfonic acid to yield 17-[N-(3-dimethylaminopropyl)imino] androst-S- en-3B-ol- 3-acetate. Reduction of these imines by treatment witha suitable chemical reducing agent such as lithium aluminum hydride or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst such as platinum oxide produces the desired 17-amiuo compounds The aforementioned 17- [N-( 3-dimethylamino propyl)imino]androst 5-en 3p-ol 3-acetate, for example, is t'reat'ed with lithium aluminum hydride to produce 17;] [N-(3-dimethylaminopropyl)amino] androst-5-en-3 3 ol. 'lhecatalytic'hydro'genation of 17-[N-(3-dimethylaminopropyn'imim] Sa-androStamSB-ol 3-acetate, pre pared by the reaction of 3'B-acetoxy-5a-androst-an-l7-one with 3-dimethylamino'pi'opylamine and p-toluenesulfonic acid, in the presence of platinum'oxide catalyst results in 3 17,8 [N-(3-dimethylaminopropyl)amino]-5 x-androstan- 35-01 S-acetate.

A preferred procedure for manufacture of t e instant compounds, wherein R of the structural representation supra is an alkyl radical containing more than one carbon atom, involves acylation of the cor-responding instant compounds, wherein R is hydrogen, suitably with a lower alkanoic acid anhydride or acid chloride in pyridine, followed by reduction of the resulting amide, for example with lithium aluminum hydride. This process is specifically illustrated by the reaction of l7B-[N-(3-dimethylaminopropyl)amino]-a-androstan-3fi-ol with acetic anhydride in pyridine to afiord'the corresponding acetamido intermediate, which is reduced by means of lithium alumi num hydride, resulting in 17,6-[N-ethyl-N-(3-dimethylaminopropyl) amino] -5 a-androstan-B 5-01.

A preferred process for manufacture of the instant compounds wherein represents an amino (NH radical involves the utilization of a compound of the structural formula CHa NHR

wherein R is hydrogen or a lower alkyl radical, and A, the dotted line, and the wavy line have the meanings e-rein-before indicated. These starting materials can be prepared by reaction of the corresponding 17-keto compound with the appropriate formamide in the presence of formic acid, followed by hydrolysis of the resulting formamido substance. Reaction of the latter intermediates with an a,B-0lefinic nitrile affords the corresponding N- cyanoalkyl derivatives. Reduction of these amino nitriles, typically with lithium aluminum hydride, affords the instant compounds of the structural formula The latter processes are specifically illustrated by the following sequence of reactions. 3fi-hydroxyandrost-5-enl7-one is heated at the reflux temperature with N-methylformamide and formic acid to yield a product, which is heated in methanol with hydrochloric acid to produce 17fl-methylaminoandrost-S-en-Bfl-ol. Reaction of this substance with acrylonitrile in the presence of an alkaline catalyst such as trimethyl benzylammonium hydroxide, yields 17,8-[N-methyl-N-(Z-cyanoethyl)amino] androst-S- en-3B-ol. This cyano compound is reduced with lithium aluminum hydride to afford the instant 17fi-[N-methyl- N- (3-aminopropyl) amino] androst-S-en-3B-ol.

A preferred process for the manufacture of the compounds of this invention, wherein Z represents a monoalkylamino radical, involves reaction of the aforementioned compounds of the structural formula NHR 011.1

with a cl1loro(lower alkanoyl) chloride to produce the corresponding 1'7-chloroalkylamido 3-chl0ro-ester. Hydrolysis of the ester function followed by reaction with a suitable primary amine affords the mono-alkylamino alkylamido compound, which is converted to the instant mono-alkylaminoalkylamino compound by reduction, suitably with lithium aluminum hydride. For example, the aforementioned l7fl-methylaminoandrost-5-en-3 8-01 is allowed to react with 2-chloropropionyl chloride to afford 1713 [N-methyl- N (Z-chloropropionyl) amino] androst-5-en-3fl-ol 3-(2-chloropropionate). Hydrolysis with aqueous potassium hydroxide in dioxane followed by reaction with methylamine affords 17B-[N-methyl-N-(2- methylaminopropionyl) amino] androst-Sen-SB-ol, which is reduced by means of lithium aluminum hydride to yield [N methyl N (3 methylaminopropyl) amino]- androst-5-en-3B-ol.

An alternate route to the instant Sa-androstane derivatives involves catalytic hydrogenation of the corresponding androst-S-enes. A specific example of this process is the reaction of 17,8-[N-methyLN-(3-diethyiaminopropyl)- amino] androst-5-en-3fl-ol with hydrogen in the presence of platinum oxide catalyst to afford 17p- [N-methyl-N-(3- diethylaminopropyl) amino] -5 a-androstan-3 fl-ol.

Equivalent to the instant amines for the purposes of this invention are the corresponding non-toxic acid and quaternary salts which are exemplified by the citrate, tartrate, maleate, ascorbate, gluconate, lactate, succinate, phosphate, sulfate, hydrobromide, hydrochloride, methiodide, ethiodide, methochloride, methobromide, methosulfate, ethosulfate, etc.

This application is a continuation-in-part of our copending application, Serial No. 98,745, filed March 28, 1961.

The compounds of this invention are useful as a result of their valuable pharmacological properties. They are, for example, anorectic agents, anti-arrhythmic agents in view of their ability to reverse atrial and ventricular fibrillations, and hypocholesterolemic agents. The quaternary salts are, in addition, hypotensive agents.

The invention is illustrated more fully by the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.). Quantities of materials are expressed in parts by weight unless otherwise noted.

Example 1 A mixture of 10 parts of 3B-hydroxyandrost-5-en-17- one, 20 parts of Z-diethyl-aminoethylamine, and 36.6 parts of formic acid is heated at 175-180 for about 8 hours, then cooled, diluted with water, and extracted with chloroform. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to afford a residue containing 17p-[N- (Z-diethylaminoethyl)formamido1androst-5-en 3B 01. To this residue is added 32. parts of methanol and 12 parts of concentrated hydrochloric acid, and the resulting mixture is heated at reflux for about 15 hours,

then cooled and concentrated to dryness in vacuo; The

residual solid is recrystallized from aqueous isopropylal It is' represented'bythe structural formula HNO HzCH:N(C: a) 3 CH3 -2HCl Example 2 A solution of 15 of 3fi-hydroxyandrost-5 en l7 one and 30 parts of 3-dimethylaminopropylamine in 3616 parts of formic acid is heated in an oil'bath at about 170 180 for about 24 hours. The cooled mixture is diluted with about 500 parts of water, and the resulting aqueous mixture is extracted with chloroform containing a-small amount of methanol. The orgahic- -layer-is washed with water, dried over anhydrous sulfate,- and evaporated to dryness underreduced' pressum.' The viscous residue is dissolved in a mixture ofliq partsofiso propyl'alco'hol and 420 parts of ether," and solution is treated with is'opropanolic hydrogen chloride. The re= sulting precipitate is collected by 'filtration' and-washed with acetone to aflord l7p-[N-'(3-dimethylaniinopropyl) -fon'rn-aanido] androst-5-en' 3pol hydrochloride. A2 solu tion of this hydrochloride {in aqueous methanol is made alkaline by the addition'of dilute aqueous sodium hydrox= ide, and the resulting colloidal precipitate isextracted= with chloroform. The chloroform." extract is washed with water, dried over anhydrous" sodiumsulfate and-"don'- centrated to dryness to aflford a residue;which -is 'crystallized from acetone, resulting in l7p-[N-(3-dimethylaminopropyDtorrnamido] androst-5-en-3fl-ol, which displays a double melting point at about 1l6'1l8 and 143l48; [a] =-67.5 (ChlOlTOfOl'Hl);

Example 3 A solution of 33 parts of 3fi-acetoxyandrost-5-en-l7- one and 20.4 parts of 3-dimethylaminopropylarnine in 350 parts of benzene is heated at reflux until the separation of water ceases; then 3.6 parts of p-toluenesulfonic acid is added, and refluxing together with water separation is continued for about 2 hours. This reaction mixture is cooled, washed with water, dried over'anhydrous potassium carbonate, and evaporated to dryness under reduced pressure. Recrystallization of the residue from hexane affords pure 17-[N-(3-dirnethylarninopropyl)imino]arrdrost-5-en-3fl-ol 3-acetate, M.P. about 86.5 885; [m] =--37 (chloroform).

Example 4 To a slurry of 4 parts of'lithium aluminum hydride in 150 parts of dioxane is added dropwise with stirring, at the reflux temperature, a solution of 10 parts of Uri-[N- (3 dimethylaminopropyl)formamido]androst-5 en-3B=o1 in 150 parts of dioxane. This reaction mixture is'hea-te'd at reflux for about 18 hours longer, then treated dropwis'e successively, at the reflux temperature, with a solution of 4 parts of water in 25 parts of dioxane, 3 parts of 20% aqueous sodium'hydroxid'e, and 14 parts of water. The resulting mixture is clarified by filtration, and the residue on the filter is washed with fresh dioxane. The filtrates are combined, evaporated to dryness under reduced pressure, and the resulting residue is recrystallized from acetone-methanol to produce 17B [N-methyl-N-(B-dimethylaminopropyl)arriino1androst-5-en-3B-ol, M.P. about 146'- 6 amine in ether-isopropyl alcohol is treated with isopropanolic hydrogenchloride to afford the corresponding dihydrochloride; [a']' =32 (methanol). It is represented by the structural formula I CHxNCHzCHzCHzN (CH3)! Example 5 To a refluxing slurry of 415 parts of lithium aluminum hydride in 250 parts of dioxane is added dropwise a solution of 31 parts of 17-[N-(3 dimethylaminopropyl)iminoJandrost-S-en-3i3-ol B-acetate in 250 parts of dioxane. Refluxing and stirring are continued for about 4 hours, after which time the mixture is--treatedsuccessive1y with 15 parts of water, 11.25 parts of 20% aqueous sodium hydroxide, and 52.5 parts of water. The insoluble salts are removed by filtration and washed with dioxane, and the filtrate is concentrated to drymess'in vacuo. Recrystallization first from aqueousethanol, then from methanol-acetone aflords-needle-like crystals of l7fi[N-(3- dimethylarninopropynaminokndrost 5 en-3B-ol, M.P. about 160-162; [a] =39.5 (chloroform). Treatment of a solution of this base in ether isopropyl alcohol with isopropanoli'c hydrogen chloride, and recrystallization of the resulti'ngprecipitate trorn aqueous isopropyl alcohol-afiords the corresponding dihydrochloride;

rsented by the structural formula CH, HNfJHzCHgCHzN (CH3):-

Example. 6

A solution of 30 parts of 3;3-hydroxy-5a-androstan-l7- one and 60 parts of 3 dimethylaminopropyl-amine in 73.2-parts ofifbrmic-acid is heated at .170l80 for about 24 hours, then cooledar'rd poured cautiously into 700 parts of dilute sodium hydroxide. The resulting aqueous mixture is extracted with'ether containing isopropyl alcohol; and the organiclayeris separated, and treated with isopropanolic hydrogen chloride. The resulting precipitate is collected-by filtration and washed with ether to yield the crude hydrochloride. Recrystallization from aqueous isopropyl alcoholafiords pure l7fl [N-(3-dirnethylaminopropyhfornramidol- 5w androstan 3/3 ol hydrochloride; [a]b=+3 (methanol); A solution of this hydrochloride in aqueous-methanolris treated with 20% aqueous sodium hydroxide, and the resulting mixture'is poured'slowly into-cold water. The-precipitate which forms is collected by filtration and recrystallized from acetone to yield 1713-[N-(3-dimethylaminopropyl)- formaniido] 5a-androstan-3fl-ol, M.P. about 148-150"; [a] =5.5 (chloroform).

Example 7 A solution of 5 partsof 17fi-[N-(3-dimethylaminopropyl)formamido] 5dandrostan-3B-ol hydrochloride in 80 parts ofeth'anol and 5' parts-of concentrated hydrochloric acid is heatedat reflux for about 6' hours. The

148; [a] =-54.5 (chloroform). A solution of this solvent is removed by distillation in vacuo and the result- 7 ing residue is crystallized from aqueous isopropyl alcohol to afiord 17p-[N-(3-dimethylaminopropyl)amino]-5a-androstan-Sfl-ol dihydrochloride; [a] +205 (methanol).

The latter aqueous isopropyl alcohol mother liquor is concentrated to dryness in vacuo, and the resulting residue is dissolved in aqueous methanol, then made alkaline with 20% aqueous sodium hydroxide, The resulting precipitate is extracted with chloroform, and the organic layer is dried over anhydrous sodium sulfate then concentrated in vacuo to afford a straw-colored oil. Crystallization of this oil from acetone-methanol results in pure 17,6 [N (3 dimethylaminopropyl)amino] 50: androstan-3fi-ol, M.P. about 149.5452", of the structural formula HNCHzCHzCHzN (CHah CH:

Example 8 The substitution of an equivalent quantity of 3-pyrrolidinopropylamine in the process of Example 2 results in 17,8- [N-(3-pyrrolidinopropyl)formamido] androst-S-en- 35-01, M.P. about135-138.

Example 9 'The substitution of an equivalent quantity of 3pyrrolidinopropylamine in the process of Example 3 results in 17 [N (3 pyrrolidinopropyl)imino]androst en-313-ol 3-acetate, M.P. about IOU-101; [a] =36 (chloroform).

Example- 10 The reduction of parts of 17-'[N-(3-pyrrolidinopropyl)imino]androst-5-en-3fi-ol 3-acetate with 10 parts of lithium aluminum hydride by the procedure described in Example 5 results in 17fi-[N-(S-pyrrolidinopropyl)- amino1-androst-5-en-3fl-ol. Recrystallization from acetone-methanol affords a pure sample, M.-P. about 164.5- 166.5; [u] =35 (chloroform).

A solution of the latter free base in anhydrous ether containing a small quantity of isopropyl alcohol is treated with isopropanolic hydrogen chloride. The resulting precipitate is collected by filtration and recrystallized from aqueous isopropyl alcohol to yield the corresponding dihydrochloride; [a] =19 (methanol).

Example 11 Example 12 A mixture of 16.5 parts of 3B-acetoxyandrost-5-en-l7- one, 9 parts of 3-morpholinopropylamine, 0.9 part of p-toluenesulfonic acid monohydrate, 20 parts of pyridine and 87 parts of toluene is distilled slowly for about 6 hours, during which time approximately 100 parts by volume of distillate is collected. The reaction mixture is cooled, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to aiford crystalline 17-[N-(3-morpholinopropyl)imino] androst-5- en-3B-ol 3-acetate. Recrystallization from hexane affords: a pure sample, M.=P. about -418"; [a] =-35.5 (chloroform) Example 13 A solution of 33.25 parts of SB-acetoxy-Sa-androstan- 17-one, 12.25 parts of 3-dimethylaminopropylamine and 1.8 parts of p-toluenesulfonic acid monohydrate in 200 parts of benzene is heated at reflux, during which time the water of reaction is removed by means of a Dean-Stark water trap. The cooled reaction mixture is washed with water, dried over anhydrous'potassium carbonate, and concentrated to dryness to afford a viscous oil consisting of l7-[N-(3-dirnethylaminopropyl)imino]-5u-androstan- 3 3-01 3-acetate. A solution of this free base in ether is treated with isopropanolic hydrogen chloride to yield the corresponding dihydrochloride; [oz] =|44.5 (methanol).

Example 14 A solution of 17-[N-(3vdimethylaminopropyl)-imino]- 5 a-androstan-3B-ol 3-acetate in 200 parts of dioxane is hydrogenated in the presence of 3 parts of platinum oxide catalyst at room temperature and about 4 atmospheres pressure until the uptake of hydrogen ceases. The catalyst is removed by filtration and washed with dioxane. Removal of the solvent from the filtrate aifords a yellow oil, which is crystallized from pentane to produce needle-like crystals of 175-[N-(3-dimethylaminopropyl)amino]-5aandrostan-3p-ol S-acetate. A solution of this free base in anhydrous ether is acidified with isopropanolic hydrogen chloride and the resulting precipitate is collected by filtration and washed with anhydrous ether. Recrystallization from aqueous isopropanol affords the corresponding di- HNCHgCHzCHgN (011:):

It is repre- Example 15 A mixture of 15 parts of 3B-acetoxyandrost-5-en-17-one, 8 parts of 2-dimethylaminoethylamine, 1.7 parts of ptoluenesulfonic acid monohydrate, and parts of ben zene is heated at reflux for about 4 hours, during which time the water formed is separated by means of a Dean- Stark water trap. The mixture is cooled and allowed to stand at room temperature for about 15 hours, then filtered to remove the precipitated p-toluenesulfonic acid salt of Z-dimethylaminoethylamine. moved by distillation in vacuo, and the residual solid is dissolved in ether, then treated with isopropanolic hydrogen chloride. The resulting hydrochloride is collected by filtration, washed with ether, and recrystallized from aqueous ethanol to afford pure l7-[N-(2-dimethylaminoethyl)imino]androst-5-en-3p-ol S-acetate dihydrochloride.

A solution of this dihydrochloride in water is made alkaline by the addition of dilute aqueous sodium carbonate. This alkaline mixture is extracted with chloroform, and the organic layer is washed with water, dried over anhydrous potassium carbonate containing decolor- [N-(Z-dimethylaminocthyl)imino]-androst 5 en-3fl-ol 3-acetate.

The solvent is re- 7 Example 16 To a solution of 3.3 parts of lithium aluminum hydride in l parts of dioxane, under nitrogen, is added, drop- I wise with stirring at the reflux temperature, a solution of 8 parts' of 17-[N-(2-dimethylaminoethyl)imino]androst- -en-3d-ol Ii-acetate in 130 parts of dioxane over a period of about 2% hours. The reaction mixture is heated at reflux for about 2% hours longer, then allowed to stand at room temperaturefor about 15 hours. The excess reducing agent is decompose'd'by the successive addition of 4 parts of water in 25 parts of dioxane, 2.5 parts of 20% aqueous sodium hydroxide, and l2 parts of water. The inorganic salts are removed by filtration and washed with dioxane. Concentration of the filtrate to dryness aifords a solid residue, which is recrystallized from acetone to produce l7fl-[N- (Z-dimethylaminoethyl) amino] androst- 5-en-3fl-ol, M.P. about 135l36 This compound is represented by the structural formula HNC HzCH2N(C H3) 2 C Ha Example 17 A mixture of one part of l7B- [N-'(2 -dimetliy lanii noethyl)amino]-androst-5-en- 3B ol, 0.25 part of platinum oxide catalyst, and 26 parts of glacial ace-tic acid is stirred in a hydrogen'atu'iosphere at room temperature and atmospheric pressure for about 2 /2 hours.- The catalyst is remoyed'by filtration, and the filtrate is concehti-ated toxafidrd' an oil. To this oil is added successively 1.5 parts'of sodium hydroxide in 19 parts of water-and 40 parts of methanol, and the resulting mixture is heated at reflux for about 10'n1'inutes, then cooled and poured into water and ice. The resulting aqueous mixture is extracted with chloroform, and the organic layer is washed with water, driedover anhydrous potassium carbonate containing decolorizing carbon and evaporated to anoil in vacuo. Crystallization from acetone produces 17B-'[N-(2 dimethylaminoethyl) amino] 51x androstan-BB-ol, M.P. about 119-122". It is represented by the structural formula HNCHzCH2N(CH3)2 CH3 Example 18 10 Example 19 To a solution of 12.8 parts of lithium aluminum hydride in 300 parts of dioxane, under nitrogen, is addedwith stirring over a period of about one hour, a solution of 31 parts of 17-[N-(3-diethylaminopropyl)am.ino]androst- 5-en-3fi-ol 3-acetate in'350 parts of dioxane. This reaction mixture is heated at reflux for about 4% hours then stored at room temperature for about 15 hours. Su

Example 20 To a solution'of 8.945' parts of l7fl- [N-(3-diethyl-aminopropyl)amino]androst-5-en-3fi+olin250 parts of glacial acetic acid is added 6 partsof' platinum oxide catalyst, and the resulting mixture is hydrogenated at atmospheric pressure and room temperature ion-about 61 hours. Filtration removes the catalyst and affords a filtrate, which is concentrated in vacuo to an oil. To this oil is added parts of methanol together with asolut'ionof 6 parts of sodium hydroxide in 25 parts o'fwater, and the resulting solution is heated at reflux for about 20 minutes, then cooled and poured into dilute aqueous sodium hydroxide. The'resulting solid is collected by filtration and extracted with chloroform. The organic layer is-W-ashed with water, dried over anhydrous potassium canbonate containing decolorizing carbon, and'concentra'ted in vacuo to yield an oil. A solution of this oil in acetone-ether is treated with isopropanolic hydrogen chloride, and the resulting salt is collected by filtration andwashed with ether, then recrystallized from-aq'ucous ethanol to produce 17,8-[N-.(3- diethylam-inopropyl)amino] -5a-androstan-3,B-ol dihydrochloride.

Crystallization from acetone of the oil obtained from the chloroform extract described in the previous paragraph, produces 1713 [N-(3-diethylaminopropyl) amino]- 5a-androstan-3B-ol, M.P. about' 'Z273 This substance is represented by the structural formula H H O H1CHzN (C2115) a OH3 Example 21 To a solution of 30 parts of 3fl-hy'droxyandrost-5 -en-17- one in 19.5 parts of formic acid is added dropwise 60 parts of 3-diethylaminopropylamine, and the resulting mixture is heated with stirring in an oil bath at -180 1 1 for about 24 hours, then cooled and poured into dilute aqueous sodium hydroxide. The precipitate which forms is collected by decantation and extracted with chloro form. The organic layer is washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon and concentrated in vacuo to afiEord an oily residue containing 173 [N-(3-diethylaminopropyl) formamido]- androst-S-en-Sfl-ol. A solution of this oil in acetone-ether is treated with isopropanolic hydrogen chloride with stirring. The resulting precipitated salt is collected by filtration, washed successively with acetone-ether and with ether, then dried to yield the corresponding hydrochloride.

Example 22 To a solution of 14 parts of lithium aluminum hydride in 250-parts of dioxane, under nitrogen, is added with stirring over a period of about 1 hours, 27 parts of 17,8- [N (3-diethylaminopropyl)formamido] androst-5-en3fi- 01 in 250 parts of dioxane, and the resulting mixture is heated at reflux for about 18 hours, then treated successively with a solution of 14 parts of water in 15 parts of dioxane, parts of 20% aqueous sodium hydroxide, and parts of water. The precipitated salts are removed by filtration, washed with dioxane, and discarded. The solvent is removed from the filtrate by evaporation at reduced pressure, and the resulting residual solid is recrystallized from acetone to produce 17fl-[N-rnethyl-N-(3-diethylaminopropyl) amino] androst-5-en-3fl-ol, M.P. about 89-91 A solution of the latter amine in anhydrous ether is treated with isopropanolic hydrogen chloride to yield the corresponding dihydrochloride salt, which is represented by the structural formula on, E30

Example 23 A mixture of 2 parts of l7fl-[N-(3-diethylaminopro pyl)amino] androst-5-en-3fi-ol, 1.34 parts of formic acid, and 1.08 parts of 36-38% aqueous formaldehyde is heated at 95-100 for about 4 hours, then heated at reflux for about 3 hours. The reaction mixture is cooled, poured into 24 parts of methanol, then made alkaline by the addition of concentrated aqueous sodium hydroxide. This alkaline mixture is heated at reflux for about 5 minutes, then poured into ice and water. The resulting aqueous mixture is extracted with chloroform, and the organic layer is separated, washed successively with water and dilute aqueous sodium hydroxide, then dried over anhydrous potassium carbonate containing decolorizing carbon. Removal of the solvent by distillation in vacuo affords an oily residue which solidifies upon standing. Recrystallization of this solid from acetone results in pure 17B- [N-methyl-N- (3-d-iethylaminopropy1)amino] androst- 5-en-3fi-ol, identical with the product of Example 22.

Example 24 A mixture of 8.91 parts of 17B-[N-methyl-N-(B-diethylaminopropyl)amino]androst 5 en-3,B-ol, 1.0 part of platinum oxide catalyst and 160 parts of ethanol is hydrogenated for about 24 hours at room temperature and about 3 atmospheres pressure. Removal of the catalyst by filtration and concentration of the resulting filtrate in vacuo aifords the desired product, obtained as the hydrochloride salt. Recrystallization of this crude material from aqueous ethanol affords a pure sample of 17fl-[N- methyl N-(3-diethylaminopropyl)amino]-5e-androstan- 3,8-ol dihydrochloride.

The crude hydrochloride is dissolved in hot water, then treated with dilute aqueous sodium carbonate. The resulting precipitate is collected by decantation, and extracted with chloroform. The chloroform extract is dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated in vacuo to yield the free base, 17,8 [N methyl N-(3-diethylaminopropyl) amino]-5a-androstan-3B-ol, M.P. about -83. It is represented by the structural formula CH NCHaCHzCHzN(C2H5)2 OH: HzC

Example 25 A mixture consisting of 25 parts of 3fi-acetoxy-androst- 5-en-l7-one, 20 parts of 3-piperidinopropylamine, 2.8 parts of p-toluenesulfonic acid monohydrate, and' 280 parts of benzene is heated at reflux for about 4 hours, during which time the water of reaction is removed. The reaction mixture is cooled, clarified by filtration, then washed with water and dried over anhydrous sodium sulfate containing decolorizing carbon. The solvent is removed by distillation in vacuo, and the resulting residual oil is crystallized from hexane to afford l7-[N-(3-piperidinopropyl)imino]androst-5-en-3fl-ol 3-acetate, M.P. about 80-82".

Example 26 To a solution of 12.8 parts of lithium aluminum hydride in 300 parts of dioxane, under nitrogen, is added dropwise with stirring over a period of about one hour, a solution of 31 parts of l7-[N-(3-piperidinopropyl)imino] androst- 5-en-3B-ol 3-acetate in 350 parts of dioxane. This reaction mixture is heated at reflux for about 4 /2 hours, stored at room temperature for about 15 hours, then treated successively with a solution of 12.8 parts of water in 50 parts of dioxane, 10 parts of 20% aqueous sodium hydroxide, and 43 parts of water. The precipitated solids are removed by filtration and washed with dioxane. The filtrate is concentrated in vacuo to afford an oil which solidifies on standing. Recrystallization of this solid from acetone produces 17,8-[N-(3-piperidinopropyl)amino]androst-5-en-3 3-ol, MP. about 141-142". A second recrystallization from acetone provides a sample melting at about 142-1425 Treatment of an ethereal solution of the latter free base with isopropanolic hydrogen chloride results in the corresponding dihydrochloride, which can be represented by the structural formula nnonzornonm Example 27 HNoHiCHmmN GE: V

-2iio1 Example 28 17-one in 732 parts of formic acid is added, with stirring and cooling, 60 parts of 3piper idinopropylamine. Tlie reaction mixture is heated for about 2 4 hours in an oil bath at a temperature o,l70 180 then cooled and poured irito dilute aqueous sodium hydroxide. flhe doughy precipita'te which forms is collected by decantation a nd e xtr'acted with chloroform; The chloroform layer is separated, washed with water,- dried over anhydrouspotassium carbonate containing;decolorizing carbon, then stripped of solvent; at reduced pressure. The oily residueis crystallized from acetone to produce "173- [N- (3 -piperidinopropyl)for'mamido] androst- 5-en-3 9l A second crystalliza'tionfromacetone provides a pure sample, melting at about 131-133.

E xa'n'i'ple 29' To a'solution .of 6.5 parts of lithium aluminum hydride in 100 parts of dio'xane,'under nitrogen, is added dropwise with stirring over ap'eriod of about 1% hours; a solution 015,13 parts of 175-[N-3-piperidinopropyl)-formamido]androst-5-en- 3fi-ol in 200 parts of dioxane. This reaction mixture is heated at reflux with stirring for about l8 hours, then treated success'iyely with 7 parts of water in 100 parts of dioxane, 6 parts of 20% aqueous sodium hydroxide and 24 parts of water. The precipitated inorganic salts are removed by filtration and washed on the filter with dioxane. Concentration of the resulting filtrate in vacuo affords a solid residue, which is recrystallized from acetone to yield 175- [N-methyl-'N-(3piperidinopropyl)amino] androst 5 en-3f3-ol, M;P. about 136- 136.5. This amine can be converted to the corresponding dihydrochloride salt by treatment of an ethereal solution with isopi'opandlic hydrogen chloride and recrystallizat'ion of the resulting solid from aqueous ethanol: dihydrochloride is represented by the structural formula onmomornomx V c 11 0 Example A mixture o'f3.85 parts of 175 [N-methyl-N-(B-piperidinopropyl)amino]androst-5-en-3/S-ol, 0.7 part of platinum oxide c'atalyst, and 160 parts of ethanol is hydrogenated at room temperature and about 3 atmospheres pressure for about 18 hours. Removal of the catalyst by filtration and the solvent by distillation in vacuo affords a solid residue, which'is dissolved in hot water. This aqueous mixture is made alkaline by the addition of dilute aqueous sodium carbonate. The resulting precipitate is separated by decantation and extracted with chloroform. The organic layer is'separated, washed with water, dried over anhydrous potassium ca'rbo'nate'containing decolorizing carbon, and concentrated to an oil by distillation of the solvent in vacuo. This oil iscrystal li'zed from acetone to produce 17B-[N-methyl-N-(3- piperidindpropyl)amino]-5d-androstan-3;3-ol,' M.P. about 134. This amine is dissolvedin ether and treated with isop ropan olic hydrogen chloride to yield a precipitate,

' which is recryt alli zed from aqueous" ethanol, resulting in the corresponding dihydrochloride, of the structural formula CH3NCH2CHtCH2N OH mo I 1 error no Example 31 To a solution of 25 parts of Sfi-acetoxyandrost-S-en- 17-one and 24 parts of 3-(N-methylpiperazino)-propylamine in 200 parts of benzene is added 2. 8 parts of ptoluenesulfonic acid monohydrate, andthe resulting mixture is heated at reflux for about 4 /2 hours with concomitant removal of water, then cooled and filtered to remove the precipitated solid. The resulting filtrate is washed with water, dried over anhydrous sodium sulfate containing decolorizing carbon, then stripped of solvent at reduced pressure. The resulting oil is crystallized from hexane to produce l7-{N-[3-(N'-methylpiperazino)propylli-rnino}androst-S-enBB-ol B-ace'tate', M.P. about 98 100".

Example 32 To a solution of 12.8 parts of lithium aluminum hydride in 300 parts of dioxane is added d'ropwise with stirring over a period of about one hour, a solution of 31 parts of 17-{N-[3-(N-methylpiperak.ino)propyl]- imino}-androst 5-en-3fi-ol B-acetate in 350 parts of dioxane. This reaction mixture is heated at reflux for about 4 hours then stored at room temperature for about 16 hours. Successive addition of a solutionof 12.8 parts of water 15 parts of dioxane, 10 parts of 20%aqueous sodium hydroxide, and 43 parts of water results in prec'ipitation of inorga'nic salts, which are separated by filtration and washed with dioxane. The filtrate'is stripped of solvent at reduced pressure to afford a solid, which recrystallized from acetone, resulting in 17fi-{N-[3- (N 7 methylpipe razinmpropyl] amino) androst-5-en-3 3-ol, M'.P. about -161". Further recrystallization from acetone yields 'a pure sample melting at about 163-16353. Treatment of an ethereal solution of this free base with isopropanolic hydrogen chloride and recrystalliaation of the resulting precipitate from aqueous ethanol produces HNCHlC HzCHzN CH3 NCH:

-3HCl Example 33 To a solution of 8.5 parts of 17p-{N-[3-(N-methylpiperazino)propyl] amino}androst 5 en-3 3-ol trihydrochloride in a mixture of 100 parts of water and 80 parts of ethanol is added 8 parts of platinum oxide catalyst. This reaction mixture is stirred under hydrogen for about 8 hours at room temperature and about 4 atmospheres pressure. The catalyst is removed by filtration, and the organic solvent is stripped by heating under reduced pressure. The resulting aqueous suspension is filtered to produce a solid, which is recrystallized from aqueous ethanol, resulting in 1713-{N-[3-(N'-methylpiperazino)- propyl] amino}-5u-androstan-3fl-ol trihydrochloride.

A solution of the latter crude trihydrochloride in water is treated with dilute aqueous sodium carbonate to afford the free base. This aqueous mixture is extracted with chloroform, and the organic layer is separated, washed with water, dried over potassium carbonate containing decolorizing carbon and concentrated to dryness in vacuo. Recrystallization of this white solid from acetone produces pure 17,8{N-[3-(N-methylpiperazino) propyl] amino}-5a-androsta.n-3fi-ol, MP. about 146-147". It is represented by the structural formula HNCH|CH3CH1N NCH; CH;

Example 34 To a solution of 20 parts of 3,8-hydroxyandrost-5en- 17-one in 61 parts of formic acid is added, with stirring and cooling 40 parts of 3-(N-methylpiperazino)-propylamine. This reaction mixture is heated at a temperature of about 175-180" for about 24 hours, then poured into dilute aqueous sodium hydroxide. The resulting aqueous mixture is extracted with chloroform, and the chloroform extract is washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated to an oil by distillation in vacuo. Crystallization of this oil from acetone produces 17p-{N-[3-(N- methylpiperazino)propyl] formamido}androst 5 en-Bfi- 01, MP. about l74-177.

Example 35 in vacuo to produce a solid. A solution of this solid in acetone-ether is treated with isopropanolic hydrogen chloride to afiord the crude hydrochloride salt. Recrystallization of this crude salt from aqueous ethanol produces 175 {N methyl-N-[3-(N methylpiperazino)propyl] amino}-androst-5-en-3p-ol trihydrochloride.

A solution of the latter trihydrochloride in hot water is made alkaline with dilute aqueous sodium carbonate, and the alkaline mixture is extracted with chloroform. The organic layer is separated, washed with water, dried over anhydrous potassium carbonate containing decoloriz i'ng carbon, and concentrated to an oil in vacuo. This oil solidifies upon standing, then is recrystallized from ace tone to afford pure 17p-{N-methyl-N-[N-methylpiper- .azino)propyl]amino}-androst 5 en-3/3-ol, M.P. about 148-149". It is represented by the structural formula onmontomonm mo Example 36 NCHs 'trihydrochloride, 1.0 part of platinum oxide catalyst, 40

parts of water, and parts of ethanol is hydrogenated at room temperature and atmospheric pressure for about 16 hours. Thecatalyst is removed by filtration and the solvent by distillation in vacuo to alford a solid residue, which is dissolved in about 300 parts of hot water. Dilute aqueous sodium carbonate is added to make the solution alkaline, and the resulting mixture is extracted with chloroform. The chloroform layer is separated, washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated to an oil in vacuo. Upon standing this oil alfords a solid, which is recrystallized'from acetone, resulting in 173- {N-methyl-N-[B-(N' methylpiperazino)propyl]amino}- 5a-androstan-3fl-ol, M.P. about 126l28.

The corresponding trihydrochloride is prepared by treatment of an ethereal solution of the free base with iso-. propanolic hydrogen chloride and recrystallization of the resulting solid from aqueous ethanol. This trihydrochloride can be represented by the structural formula CH NGI-IzCHAJH N Ncm orrt- Hi0 Example 37 To a solution of 20 parts of 3fi-hydroxyandrost-5-en- 17-one in 48.8 parts of formic acid is added, with stirring and cooling, 40 parts of 2-dimethylaminoethylamine. The resulting mixture is heated at l80 for about 24 hours, then poured into 120 parts of methanol. Dilution of this mixture with 1500 parts of water containing 40 parts of sodium hydroxide results in precipitation of a sticky solid, which is collected by filtration and extracted with chloroform. The organic layer is separated, washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon and evaporated in vacuo to afiord an oily residue. A solution of this oil in acetone-ether is treated with isopropanolic hydrogen chloride,

. 1-7 and the resulting precipitated salt is collected by filtration washed with ether and dried to produce "1713- [N-'(2'-'dimethylaminoethyl)formamido]androst-5-en-3p ol hydrochloride. The pure hydrochloride is obtained by recrystallization from aqueous ethanol.

A solution of the latter hydrochloride in hot water is made alkaline by the addition of dilute aqueous sodium hydroxide. The liberated free base'is extracted into chloroform, and the chloroform extract is washed with water, dried over potassium carbonate {containing decolorizing carbon, and stripped of solvent under reduced pressure to yield an oil, which upon recrystallization from acetone, afiords pure 17B-[N(2-dimethylaminoethyl)formamido] androst-S-en-BB-ol, M.P.-ab'out T58159.

Example 38 To --a JSOIUtiOH of-4.5 parts of 'litbium 'alurninumihydride in 2100 parts of di'oxane, under-nitrogen, is added dropwisewith stirring over .a period-bf about 1 5' minutes, a solution of '9'parts'of 173'-[N-(2 dimethylaminoethyl)' form amido]androst-5-en-3p-olTin160 parts "of dio'xane. The reaction mixture is heated atrreflux for about 18 hours, allowed to stand at room 'temperature for about 16 hours, then treated successively-with 4Z5 parts-of-water in partso'f dioxane, 3.5 parts-of 20% aqueous'soiliumhydroxide, and ZO'partsof water. The resulting insoluble'inorganic-salts are 'removefl by'filtration andvvasltedwi-th dimetric. The filtrate i's coneentrated to'dryness atrediicd pressure and the residual solid isTecrystallized from face tone. -"A'solution of this material in adetone ether is treated dr'opwise with isopropanolic hydro'gen z'zliloride, and the='res1ilting solid*i s -'colleeted by filtration and dried to produce '17-B [Nme'thyl -"N CZ dimethyIaminO'tHYI) amind] androst i 5 ch 3B-iil'ilihyklro'hlo"ride, which is represented 'by the structural formula enmomenmrcna, -oH. Q

"Example 39 ornNcmomoHniwm 1- CH: H

Example 40 The substitution of an equivalent quantity of 17;?- [N-(3-morpholinopropyl)imino] androst-5-en-3fl-ol 3-ace- 18' tate in the process ofExarnple 5 results in 17/8-[N-(3- anotpholirropropylyaniino] androst 5 en-3B-o1whieh is represented by the structural-formula I CH:

Example 41 'By substituting anequivalent'quantity of 17-[N-(3- morpholiriopropyflirnino]androst 5 'en 33 ol '3-aceta'te an d dtherwise proceeding according to the method described in Example 14, 17,8-[N-(3-morpholinopropyl) amino]-5a-androstan-3fi-ol 'S-acetate is obtained. This substance canbe represented by the structural formula CH: HNCHzCHgCHzN .2)

Example 42 An equivalent quantity of 3B-propionoxy-Sa-androstanl7-0ne is substituted in the process described in Example 13 to produce 17-[N-(S-dirnethylaminopropyl)imino]-5a- 4b androstan-Sfl-ol 3-propionate.

Example 43 CHaOHiOO O 5 Example 44 A solution of 15 parts of 3a-hydroxy 5a-androstan-17- am and 220jparts of'ben'zene is subjected to distillation to remove any-moisture. To this anhydrous solution is a'rlded"9.4parts of 3-dimethylam'inopropylamine and 1.7 parts ofp-toluenesulfo'nic' acid, arid the resultingvreaction mixture is heated at reflux "for about "5 hours, during which'time the 'watero'f reaction is removed. azeotropically. The solution isthlencooled, washed with :water, dried lization from acetone-hexane yields 17- [N-(3-dimethylaminopropyDir'riino'] -'5a androstan-Ba-OI, NLP. about -136".

19 Example 45 To a mixture of 6.2 parts of lithium aluminum hydride and 155 parts of purified dioxane, under nitrogen, is added, with stirring over a period of about 1 hours, a solution of 16 parts of 17-[N-(3-dimethylaminopropyl)- imino] -a-androstan-3a-0l in 155 parts of dioxane. The stirred mixture is heated at reflux for about 4 hours, then is cooled and treated successively with a solution of 6.2 parts of water in 31 parts of dioxane, 5 parts of 20% aqueous sodium hydroxide, and 21 parts of water. The precipitated salts are removed by filtration and washed on the filter with dioxane. Removal of the solvent from the filtrate by distillation affords a residue, which is dissolved in anhydrous ether and treated with isopropanolic hydrogen chloride. The resulting precipitate is collected by filtration and recrystallized from aqueous isopropyl alcohol to produce 17,8-(3-dirnethylaminopropyl)amino-5u-androstan-3 -ol dihydrochloride.

Example 46 A solution of one part of l7fl-(3-dimethylarninopropyl)amino-5a-androstan-3a-ol dihydrochloride in 50 parts of water is treated with aslight excess of 10% aqueous sodium carbonate, and this alkaline mixture is extracted with chloroform. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Recrystallization of the? residue from aqueous acetone produces l7fl-(3-dimethylaminopropyl)amino- 5a-androstan-3a-ol, M.P. about 110 111". It is represented by the structural formula HNCHzCHzCHzN (CH3)! CH:

Example 47 To a mixture of 10 parts of 3a-hydroxy-5a-androstan- 17-one and 30 parts of formic acid is added cautiously, 20 parts of 3-dimethylaminopropylamine, and the resulting mixture is heated at reflux for about 22 hours. This solution is cooled, then neutralized with a solution of 10 parts of sodium hydroxide in 250 parts of water. The resulting precipitate is collected by filtration, washed with water, and recrystallized from acetone to yield 17B-[N- (3-dimethylaminopropyl)formamido1-5a androstan 3aol, M.P. about 138139.5.-

Example 48 To a mixture of 5 parts of lithium aluminum hydride and 103 parts of purified dioxane, under nitrogen, is added dropwise over a period of about 1 hour, with stirring, a solution of 7 parts of 17B-[N-(3-dimethylaminopropyl)formamido]-5a-androstan-3a-ol in 77 parts of dioxane. This mixture is heated at reflux for about 20 hours, then is cooled and treated successively with a solution of 5 parts of water in 20 parts of dioxane, 4 parts of 20% aqueous sodium hydroxide, and 19 parts of water. The precipitate which results is removed by filtration and washed on the filter with dioxane. The filtrate is concentrated to dryness to yield a white solid, which is recrystallized from acetone, resulting in 17s- [N-methyl N-(3-dimethylaminopropyl)aminoJ-Sa an- 20 drostan-Sa-ol, M.P. about 133l34.

It is represented by the structural formula CHgNCHrCHzCHzN (CH3):

Example 49 Example 50 To a solution of 15 parts of 3p-hydroxyandrost-5-en- 17-0ne in 36.6 parts of formic acid is added, with stirring over a period of about 10 minutes, 30 parts of 3-methyl aminopropylarnine. This reaction mixture is heated at reflux for about 24 hours, then is cooled and poured cautiously into a solution of 20 parts of sodium hydroxide in 500 parts of Water. The precipitate which forms is collected by filtration, then is extracted with chloroform. The chloroform solution is washed with water, dried over a mixture of anhydrous potassium carbonate and decolorizing carbon, and concentrated to afford an oily residue, which is dissolved in acetone and treated with isopropanolic hydrogen chloride to afford crude 17p- [N- (3 methylaminopropyDformamido] androst 5-en 319-01 hydrochloride. This crude salt is dissolved in water, and the aqueous solution is made alkaline by the addition of dilute aqueous sodium carbonate. The resulting precipitate is separated by centrifugation, then is washed with water and is extracted with chloroform containing a small proportion of methanol. This organic extract is dried over potassium carbonate, and the solvent is removed by distillation to afford an oil. This oil is dissolved in acetone and treated with isopropanolic hydrogen chloride to yield pure 17fi-[N-(3-methylaminopropyl)formamido] androsat-S-en-Sfi-ol hydrochloride.

Example 51 To a mixture of 5.8 parts of lithium aluminum hydride and parts of dioxane, under nitrogen, is added with stirring over a period of about 30 minutes, a solution of 11 parts of 17p-[N-(3-methylaminopropyl) formamid0]androst-5-en-3/3-ol in 103 parts of dioxane. This mixture is heated at reflux for about 18 hours, then is cooled and treated successively with a solution of 5.8 parts of water in 20 parts of dioxane, 5 parts of 20% aqueous sodium hydroxide, and 20 parts of water. The precipitated salts are removed by filtration and washed with dioxane. Distillation of the solvent from the filtrate yields an oil, which is crystallized from acetone to afiord 17B [N-rnethyl N-( 3 methylarninopropyl)amino]androst-S-en-IaB-oil, M.P. about 121-125 This compound is represented by the structural formula CHgNCH CHaCH NHCH;

CH: H30

21 Example 52 The reaction of one part of 1713-[N-methyl-N-(3-methylaminopropyl)amino]androst--en-3fl-ol with isopropanolic hydrogen chloride according to the procedure of Example 49 results in 175-[N-methyl-N-(3-methylaminopropyl)amino]androst-5-en-3 3-01 dihydrochloride.

Example 53 The substitution of 11.5 parts of 17/3-[N-(3-dimethylaminopropyl)formamido]-5u-androstan-3B-ol in the procedure of Example 51 affords l7fl-[N-methyl-N-(3-dimethylaminopropyDamino] 5a androstan-Iifi-ol, M.P. a-bout 1345-1355". It can be represented by the structural formula Example 54 The substitution of one part of l 7fi-[N-methyl N-(3- dimethylaminopropyl)amino]-5a-androstan 3p-ol in the procedure of Example 49 results in 17fi-[N-methyl-N-(3- dimethylaminopropyl)amino] 5a androstan-3fl-ol dihydrochloride.

Example 55 A mixture of 50 parts of 3p-hydroxyandrost-5-en-17- one, 50 parts of Nmethy1formamide and 61 parts of formic acid is heated at reflux for about 20 hours, then is cooled and poured into 2500 parts of water containing 50 parts of sodium hydroxide. The resulting precipitate is collected by filtration, dried on the filter, then extracted with chloroform. The organic extract is washed with water, dried over anhydrous potassium carbonate containing decolorizing carbon, then evaporated to dryness to afford a white solid residue. I

A mixture of 51 parts of the latter residue with 360 parts of methanol, 178.5 parts of concentrated hydrochloric acid, and 150 parts of water is heated at reflux on the steam bath for about 3 hours, then is concentrated to dryness in vacuo. The resulting solid is dissolved in hot Water, and this aqueous solution is poured into a solution of 50 parts of sodium hydroxide in 2,000 parts of water. The precipitate which forms is collected by filtration, washed with water, dried on the filter, then recrystallized from acetone to yield 17B-(N-rnethylamino)androst-5-en-3fl-ol, M.P. about 189-194".

Example 56 The substitution of 50 parts of 3B-hydroxy-5u-androstan-l7-one in the procedure of Example 55 results in 17fi(N-methylarnino)-5a-androstan-3fi-ol, M.P. 211-212.

Example 57 To 20.3 parts of acrylonitrile is added portiouwise, over a period of about 30 minutes, 7 parts of 17fi-(N- methylamino)androst-5-en-3}3-ol. To this mixture is added 0.2 part of trimethyl benzyl ammonium hydroxide, and this reaction mixture is heated on the steam bath for about 16 hours. The excess acrylonitn'le is distilled in vacuo to afford a semi-solid residue containing 17fi-[N. methyl-N-.( 2-cyanoethyl amino] androst-i-emlfl-ol.

The latter residue is dissolved in 75 parts of purified about dioxane, and the resulting solution is added dropwise over a period of about one hour, with stirring, to a mixture of 4 parts of lithium aluminum hydride with parts of purified dioxane. This reaction mixture is heated at reflux for about 18 hours, then is treated successively with 4 parts of water in 30 parts of dioxane, 3 parts of 20% aqueous sodium hydroxide, and 13.6 parts of water. The precipitated salts are removed by filtration and washed on the filter with dioxane. The filtrate is stripped of solvent to afford a residue, which is recrystallized from acetone to produce 17B-[N-methyl-N-(B-aminopropyl)- amino] androst-5-en-3fl-ol of the structural formula Example 58 C'HJNCHICHCHINHI on.

Example 59 A mixture of 4 parts of 17B-(3-dimethylaminopropyl)aminoandrost-5-en-3p-ol, 21.6 parts of acetic anhydride, and 40 parts of pyridine is stored at room temperature for about 18 hours, then is poured into 350 parts of water containing 20 parts of sodium acetate. This aqueous mixture is made alkaline by the addition of concentrated aqueous sodium carbonate, and the resulting precipitate is collected by filtration to afford 17B-[N-(3- dimethylaminopropyl) acetamidoJandrost 5-en-3,B ol 3- acetate.

Treatment of a solution of the latter amine in ether with isopropanolic hydrogen chloride followed .by recrystallization of the resulting solid from acetone results in 171?- [N- 3-dimethylaminopropyl) acetamido] androst- 5-en-3,B-ol 3-acetate hydrochloride.

Example 60 To a mixture of 1.6 parts of lithium aluminum hydride in 40 parts of dioxane is added over a period of about 1% hours, with stirring, a solution of 3.2 parts of 1718-[N-(3- dimethylaminopropyn'acetamidolandrost-S-en 3p ol 3- acetate in 40 parts of dioxane. The reaction mixture is heated at reflux for about 18 hours, then is treated successively with 1.6 parts of water in 15 parts of dioxane, 1.3 parts of 20% aqueous sodium hydroxide, and 6 parts of water. The precipitated salts are removed by filtration and washed with dioxane. Distillation of the solvent from the filtrate aflords an oil, which solidifies on standing. Recrystallization from acetone yields 17fi-[N- ethyl-N-(3-dimethylaminopropyl) l'androst-S-en 3p ol,

23 M.P. about 97-100. It is represented by the structural formula CzH NCH2C HzCHzN H3) on H30 Example 61 A solution of 1 part of 17,8-[N-ethyl-N-(3-dirnethylaminopropyl) amino] androst-5-en-3fl-ol in 20 parts of acetone is treated with isopropanolic hydrogen chloride to afford the corresponding dihydrochloride.

Example 62 By substituting 30 parts of 2-ethylaminoethylamine and otherwise proceeding according to the processes of Example 50, 17B-[N-(2-ethylaminoethyl)formamido]androst-5-en-3fl-0l hydrochloride is obtained.

Example 63 The substitution of 11 parts of l7B-[N-(2-ethylaminoethyl)formamidol androst-S-en-BB-ol in the procedure of Example 51 results in 175-[N-methyl-N-(2-ethy1aminoethyl) amino] androst-5-en-3B-ol of the structural formula CHgNCHgC H NHCzHs on: H30

Example 64 By substituting 25.7 parts of crotononitrile and otherwise proceeding according to the processes of Example 57, 175-[N-methyl-N-(3-an1ino l methylpropyl)amino]androst-5-en-3fl-ol is obtained. It is represented by the structural formula orrmonomorrmn, H3O t CH:

Example 65 By substituting 3.4 parts of 17,3-[N-(3-dimethylaminopropyl)propionamidol androst-S-en 3B o1 S-propionate and otherwise proceeding according to the processes of Example 60, 17p-[N-n-propyLN-(B:-dimethylaminopropyl) amino] androst5-en-3B-ol is obtained. resented by the structural formula It can be rep- CH OHzCHzNCHaCHaCHzN(CH3)a CH3 11,0 I

Example 67 Thereaction of 10 parts of 3fi-hydroxyandrost-5-en-17- one, 20 parts of 4-dimethylaminobutylamine, and 24.4 parts of formic acid according to the procedure of Example 2, followed by recrystallization of the crude product from methanol-acetone, results in 17fl-[N-(4-dimethylaminobuty1)formamido]androst-S-en-Bfl-ol, M.P. about 184-187"; =-57 (methanol).

Example 68 Example 69 The substitution of 2.2 parts of 17fi-[N-methyl-N-(4- dimethylaminobutyDamino] androst-5-en-3fl-ol in the procedure of Example 49 affords a product which is recrystallized from aqueous ethanol-butanone to afford pure 1713 [N methyl N (4 dimethylaminobutyl) amino]androst-5-en-3fl-ol dihydrochloride.

Example 70 To a solution of 15.2 parts of l7fl-(N-methyl'amino) androst-5-en-3B-ol in 250 parts of benzene containing 7.3 parts of triethylamine is added dropwise a solution of 16.9 parts of 2-chloropropionyl chloride in 50 parts of benzene. This reaction mixture is heated at reflux with stirring for about one hour, then is cooled and filtered. The filter cake is washed on the filter with benzene, and the washings are combined with the filtrate. The benzene solution is then washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and water, and is dried over anhydrous sodium sulfate. Concentration to dryness of this solution afifords 17,8-[N-mcthy1- N (2-chloropropionyl) aminoTandrost 5 en 3,6 ol 3-(2-chloropropionate).

To a solution of 48.4 parts of 17fi-[N-methyl-N-(2- chloropropionyDamino] androst 5 en 3p ol 3 (2 chloropropionate) in 300 parts of dioxane is added a solution of 6 parts of potassium hydroxide in 2 parts of water. This reaction mixture is kept at room temperature for about 18 hours, then is diluted with water and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness, resulting in 17fl-[N-methyl-N-(2-chloropropionyl) amino] androst-5-en-3 5-01.

Example 71 To a solution of 7.8 parts of 17p-[N-methyl-N-(2- chloropropionyl)amino] androst-S-en-BB-ol in 100 parts of toluene containing 23 parts of butanone is added a solution of 6.2 parts of methylamine in 25 parts of toluene. This reaction mixture is heated in a sealed container for about 40 hours, then is cooled, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure to yield 17B-[N-methyl-N-(2- methylaminopropionyl) amino] androst--en-3p-ol.

Example 72 To a slurry of 3.8 parts of lithium aluminum hydride in 75 parts of purified dioxane is added, with stirring a solution of 7.69 parts of 1713-[N-methyl-N-(Z-methylaminopropionyDamino]androst-5 en-3B-ol in 100 parts of purified dioxane. This reaction mixture is heated at reflux with stirring for about 18 hours, then is cooled in an ice bath and treated successively with 50 parts of dioxane containing 4 parts of water, 3 parts of 20% sodium hydroxide and 14 parts of water. The precipitated salts are removed by filtration and washed on the filter with dioxane. The filtrate is concentrated to dryness -to yield 17B-[N-rnethyl-N-(3-methylaminopropyl)amino] androst-5-en-3B-ol.

Example 73 The substitution of 9 parts ofi ethylamine in the procedure of Example 71 results in l7p [N methyl-N-(2- ethylaminopropionyl)amino]androst-S-en-Zifl-ol.

Example 74 By substituting 7.97 parts of 175- [N-methyl-N-(Z- ethylaminopropionyl)amino] androst 5 en 3p 01 and otherwise proceeding according to the procedure of Example 72, 17 81[N-rnethyl-N-(3-ethylaminopropyl)amino] androst-5-en-3fi-ol is obtained.

Example 75 CHaNCHICHzCHzN CHz H3C I What is claimed is: 1. A compound of the structural formula CHa H O wherein A is selected from the group consisting of hydrogen and lower alkanoyl radicals, R is selected from the group consisting of hydrogen and lower alkyl radicals, Alk is a lower alkylene radical containing more than one and N (X) n radicals, wherein R' and R are selected from the group consisting of hydrogen and lower alkyl radicals, X is selected from the group consisting of methylene, epoxy,

and methylimino radicals, and n is selected from the group consisting of 0 and 1.

2. A compound of the structural formula wherein Alk is a lower alkylene radical and R, R, and R l are lower alkyl radicals.

3. A compound of the structural formula RN-Alk-N HO Mv wherein Alk is a lower alkylene radical and R, R, and R are lower alkyl radicals.

4. A compound of the structure formula wherein Alk is a lower alkylene radical and R and R" are lower alkyl radicals.

5. A compound of the structural formula HO AM! wherein Alk is a lower alkylene radical and R and R" are lower alkyl radicals. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 